JPH0517457A - Benzisothiazole and benzisoxazole piperazine derivative - Google Patents

Abstract

PURPOSE: To prepare a new intermediate compound useful for synthesizing a piperazinyl derivative having excellent psychotropic (antipsychotic) activity.

CONSTITUTION: A piperazine heterocyclic compound of formula I (Y is O or S; Z is H or a halogen), such as 3-(1-piperazinyl)-1,2-benzisothiazole is prepd. This compound is obtd. by bringing 3-chloro-6-Z-1,2-benzisothiazole or 3-chloro-6- Z-1,2-benzisothiazole to react with excessive piperazine at a raised temp. The intermediate of formula I is brought to react with a compound of the formula Imid-A {A is (CH₂)_n-X {(n) is 3 or 4; X is the acid residue of a reactive ester} Imid is formulae II to V [R¹ and R² are each an alkyl or together form (CH₂)₄ or (CH₂)₅]}, by which a piperazinyl derivative having strong psychotropic acitivity is obtd.

COPYRIGHT: (C)1993,JPO

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates generally to heterocyclic carbon compounds having drug and biological properties, as well as intermediates and uses for their preparation. One substitution is 1,
2-benzisothiazol-3-yl or 1,2-benzisoxazol-3-yl, and the other is a heterocycle (linked via an alkylene chain) or butyrophenone analogue (and the corresponding) The 1,4-di-substituted piperazine derivative which is a carbinol) group is a useful drug.

[0002]

[Chemical 2]

Wu US Pat. No. 3,398,1
51 and Wu et al., U.S. Pat. No. 3,717,634 and corresponding Wu et al. Med. Chem., Vol. 12, pp. 876-
881 (1969), Volume 15, 447-479.
On page (1972), various azaspiro [4.5] decanedione and dialkylglutarimide psychotropic compounds similar to the following formula (1) are described.

[0004]

[Chemical 3]

In the above formula, R ¹ and R ² are alkyl or combined to form-(CH ₂ ) ₄ --or-(CH ₂ ) _5- , and B is especially phenyl plus various heterocycles. (Both have optional substitutions):

[Chemical 4] Indicates.

US Pat. No. 4,182,763 to Casten et al. Is buspiron.
e) relates to the anxiolytic use of compound (4) described in the biological literature.

[0007]

[Chemical 5]

Benica et al. Am Pharmaceuticals Association (J. Am.
Pharmaceutical Associate
n), pp. 451-456 (1950), as shown in formula (3), 3,3-dialkylglutarimide (R ¹ is C
₁ - a ₄ alkyl, and R ² is hydrogen or C ₁
- ₄ alkyl as) disclose, and these compounds are said to be lacking remarkable physiological activity.

[0009]

[Chemical 6]

Thiazolidinediones are known in the art. For example, Jones is J. Chem
Sok London (J. Chem. Soc., London
n) pp. 91-92 (1946) describe 5,5-dialkyl-2,4-thiazolidinedione barbituric acid analogues, and in 5-spirocyclohexyl-2,4-thiazolidinedione (4) gamous It is described as producing anesthesia and analgesia.

[0011]

[Chemical 7]

Various types of 1,4-substituted piperazine derivatives are also known in the art, as exemplified in the following references: British Patent No. 2,023,594A discloses 1- (R-alkyl) -4- (3-trifluoromethylthiophenyl) useful for treating anxiety and depression having the general formula (5): Piperazine is disclosed.

[0013]

[Chemical 8] Wherein n is 1-3, and R is especially a heterocycle

[0014]

[Chemical 9] Where m is 0 or 1 and X is -S-,
Represents -O-, imino, alkylimino or methylene). Rojsner, etc. are collect, collect, comm, and collect.
ch. Chem. Commun. ), Volume 40 (4),
Pages 1218 to 1230 (1975) disclose the butyrophenone derivative of the following formula (6) as a part of the psychotropic structure-activity relationship study.

[0015]

[Chemical 10]

The above-mentioned documents all refer to the
No 2-benzisothiazole or 1,2-benzisoxazole piperazine derivatives are disclosed or suggested. In its broadest aspect, the invention provides a piperazinyl derivative having a potent tranquilizing action or a pharmaceutically acceptable non-toxic acid addition salt thereof, which is characterized by a compound having the formula (I): .

[0017]

[Chemical 11]

In the formula, R is a group

[Chemical 12] Where n is 3 or 4 and R ₁ and R ₂ are independently lower alkyl having 1 to 4 carbon atoms.
Where Y is oxygen or sulfur and Z is hydrogen or halogen).

Halogen as used herein means fluorine, iodine and preferably chlorine and bromine, and the term "lower alkyl" refers to straight and branched chain carbon groups having 1 to 4 carbon atoms. Examples of these groups are methyl, ethyl, propyl, isopropyl, 1-
A carbon chain that can be butyl, 1-methylpropyl and 2-methylpropyl.

The pharmaceutically acceptable acid addition salts according to the invention are those in which the anions do not contribute significantly to the toxicity or pharmacological activity of the salt, and the salts themselves are those of the bases of formula (I). It is a pharmacological equivalent. These salts are generally preferred for medical use. In some cases, these salts have physical properties that make them more desirable for pharmaceutical formulations, such as solubility, lack of hygroscopicity, compressibility for tablet making, and compatibility with other ingredients by which the substance may be used for pharmaceutical purposes. have. The salts are usually prepared by mixing the base of the formula (I) with the selected acid, preferably using an inert solvent which is usually used such as water, ether, benzene, ethanol, ethyl acetate and preferably an excess of acetonitrile. It is produced by contacting in solution. These salts are also provided under conditions in which the anion of one salt of the substance of formula (I) allows the separation of the desired species, for example by precipitation from solution or extraction into a solvent or elution or retention from an ion exchange resin. It can also be produced by substitution or treatment with an ion exchange resin under conditions such that it is substituted with another anion below. Pharmaceutically acceptable acids for the salt formation of substances of formula (I) include sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, citric acid, acetic acid, benzoic acid, cinnamic acid, mandel. Acids, nitric acid, mutic acid, isothionic acid, palmitic acid, hepatonic acid and the like are included.

The compounds of formula (I) in which R is a group of "a, b, c and d" of the present invention are described in the patents of Wu et al. Above which include alkylation of piperazinyl or "imide" intermediates. It is obtained by a method similar to that of. The entire patent is incorporated into the text for reference. Such a method is preferred for compounds of formula (I) (R = a, n = 4, Y = S, Z =
H) ie 8- [4- [4- (1,2-benzothiazol-3-yl) -1-piperazinyl] butyl] -8-
The production of azaspiro [4.5] decane-dione (I _a1 ) is exemplified below.

[0022]

[Chemical 13]

[0023]

[Chemical 14]

In the above reaction scheme, M represents an alkali metal salt, and the particular halogens listed are operable halogen groups (eg chlorine, bromine, iodine) and suitable substituents such as sulfate, phosphate, tosylate,
It is provided only as an example of another member, such as rice silicate. Method A generally involves the use of the group “a,
b, is described as a process for preparing compounds of c and d "in which formula (I), in this method the formula (II) Imid-A (II ) [wherein, A is - (CH _{2) n} -X, Where n is 3
Or 4 and X is an acid residue of a reactive ester group such as chloride, bromide, iodide, fluoride, sulphate, phosphate, tosylate or mesylate, and Imid is

[0025]

[Chemical 15] Wherein R ₁ and R ₂ are independently lower alkyl] and have the formula (III)

[0026]

[Chemical 16] (Wherein Y is oxygen or sulfur and Z is hydrogen or halogen) in an inert reaction solvent.

Method B is more generally described as a process for the preparation of compounds of formula (I) wherein R is a group "a, b, c and d" as defined above, which process is of formula (IV) Imid-M. (IV) where M is an alkali metal salt such as sodium, potassium or lithium, and Imid is

[0028]

[Chemical 17] Wherein R ₁ and R ₂ are independently lower alkyl) and have the formula (V) or (V ′)

[0029]

[Chemical 18] Where X is an acid residue of a reactive ester group such as chloride, bromide, iodide, fluoride, sulfate, phosphate, tosylate or mesylate, and in formula (V ') is preferably bromine, chlorine or iodine, n is 3 or 4, Y is oxygen or sulfur, and Z is hydrogen or halogen.)
It is characterized in that it is reacted with a compound having

Process C is more generally described as a process for the preparation of compounds of formula (I) wherein R is a group "a, b, c and d" as defined above, which process is represented by formula (VI)

[0031]

[Chemical 19] (Where Imid is

[0032]

[Chemical 20] Wherein R ₁ and R ₂ are independently lower alkyl, and n is 3 or 4)

[0033]

[Chemical 21] Characterized in that halo is halogen, preferably chlorine or bromine, and Y is oxygen or sulfur, and Z is hydrogen or halogen, and is reacted in an inert reaction solvent. .

Process D is generally described as a process for the preparation of compounds of formula (I) wherein R is a group "a, b, c and d" as defined above, which process is represented by formula (VIIIa, b, c or d)

[0035]

[Chemical formula 22] An anhydride having the formula: wherein R ₁ and R ₂ are independently lower alkyl is represented by the formula (IX)

[0036]

[Chemical formula 23] (Wherein n is 3 or 4, Y is oxygen or sulfur, and Z is hydrogen or halogen) and is reacted in an inert reaction solvent.

The general embodiment of the above methods A, B and C is the compound of formula (III), (IV) or (VI) in an inert reaction solvent, represented by formula (II), (V), (V ' ) Or (VII) wherein R is a group “a, b, c and d” as defined above, characterized in that it is reacted with an alkyl intermediate of formula (I)
Constitutes a single method of producing the compound of

Methods A and C are usually carried out under the reaction conditions used in the preparation of tertiary amines by alkylating secondary amines. That is, R is a group "a, b,
The compounds of formula (I) which are "c and d" are prepared by reacting a suitable intermediate in an inert reaction medium at a temperature of about 50 to 200 ° C in the presence of a base suitable for use as an acid binder. can get. Operable inorganic and organic acid-binding bases include tertiary amines, alkali and alkaline earth metal carbonates, bicarbonates or hydrates, sodium carbonate and potassium carbonate being particularly preferred. As used throughout the text, the term "inert reaction medium" refers to any protic or aprotic solvent or diluent that does not participate in the reaction to any substantial extent. In this regard, acetonitrile is a particularly preferred solvent,
The reaction is conveniently carried out at the reflux temperature. Satisfactory yields of the compounds of the invention are obtained with reaction times in the range of about 2-24 hours. The product of formula (I) is purified by crystallization techniques from standard solvent systems such as acetonitrile, isopropanol, methanol and the like and by conventional methods such as chromatography using silica gel columns with a mixture of chloroform and alkanols such as methanol and ethanol as solvent. can do.

Process B is a modification of the single process of the invention for preparing compounds of formula (I) in which R is a group "a, b, c and d", in which the imide of formula (IV) is The intermediate alkali metal salt is alkylated. Standard laboratory procedures, such as Gabriel, are used to carry out this reaction.
Description method for synthetic alkylation step-S. Gabriel, Ber, Volume 20, pages 2224, 188
7 years-use. For example, in this example, the reaction agent is 50 to 2
Bonding is carried out in an inert reaction medium at a temperature in the range of 00 ° C.
Toluene and xylene are particularly suitable solvents for carrying out the reaction, but other solvents which do not adversely affect the reaction or the reactants can be used. In this regard, solvents such as dioxane, benzene, dimethylformamide, acetone, acetonitrile, n-butanol and the like can be manipulated. Generally, the alkali metal salt (IV) is obtained by converting the corresponding imide precursor into an alkali hydride such as sodium hydride, an alkali alcoholate such as sodium methoxide, an alkali amide such as sodium amide, an alkali base such as sodium hydroxide, potassium hydroxide,
It is prepared by treatment with an alkali carbonate such as sodium carbonate or potassium carbonate in a suitable solvent. It is not necessary to pre-form the alkali metal salt of formula (IV) and the imide precursor and the piperazinyl alkylating agent (V or V ') are added in a base, preferably sodium or potassium carbonate, in an inert reaction medium. Can be conveniently combined with.

Compounds of formula (I) in which R is a group "e or f" have formula (III)

[0041]

[Chemical formula 24] A piperazinyl intermediate having the formula (X) in an inert reaction solvent, wherein Y is oxygen or sulfur and Z is hydrogen or halogen.

[0042]

[Chemical 25] Alkylation with a compound having the formula (Ie), wherein X is as defined above, most preferably chlorine or bromine.

[0043]

[Chemical formula 26] To obtain a compound having, then (Ie) is reduced to (I
f)

[0044]

[Chemical 27] Obtained by a method comprising obtaining the corresponding compound having

The piperazinyl benzisothiazole and benzisoxazole intermediates of formula (III) can be treated with 3-chloro-6-Z-1,2-benzisothiazole or 3-chloro-6-Z- at elevated temperature. Obtained by reacting 1,2-benzisoxazole with excess piperazine. For example, the 3-chloro-1,2-benzisothiazole starting material is 1,2-benzisothiazole-3 (2
H) one is prepared by treating phosphorone pentachloride for 4 hours at 100-140 ° C. Similarly, the conversion of 1,2-benzisoxazol-3-one to 3-chloro-1,2-benzisoxazole is Boshagen (Bosha).
Gen) -Ber, Volume 100, 33
P. 26, 1967-with phosphorus oxychloride / triethylamine.

The compounds obtained according to the invention are useful pharmacological agents with psychotropic activity. In this regard, the compounds obtained according to the invention show a selective central nervous system action at non-toxic doses and are potent psychotropic (psychotropic).
I am particularly interested in the drug. Like other known potent tranquilizers, the compounds of formula (I) are known to correlate well with anxiety and symptomatic relief of acute and chronic mental illness in the human body in standard in vitro and in vitro test systems. To induce a reliable reaction. Specific examples of routine in vivo tests used to classify and distinguish between non-specific CNS inhibitors and psychotropic agents and to measure potential side-effect trends (eg, catalepsy activity) are shown below. Regarding the latter side-effect tendency, it is known that psychotropic drugs as a group produce sedation and extrapyramidal system reactions such as acute myotonic tone, long-standing orthotopic incompetence, Parkinson's syndrome, late-onset dyskinesia and autonomic nervous system effects. Has been.

[0047]

[Table 1]

As a further indicator of the psychoactive activity and specificity of the compounds obtained according to the invention, the state of the art in vitro central nervous system receptor binding methodologies can be used. It has been determined that certain compounds, commonly referred to as ligands, bind preferentially to specific high affinity sites in brain tissue processing psychoactive or potential side effects. Inhibition of isotope-labeled ligands bound to such specific, high-affinity sites is believed to be a measure of a compound's ability to affect corresponding central nervous system function or cause side effects in vivo. This principle is used in the following assay method, which is provided for illustration.

[0049]

[Table 2]

According to the pharmacological profile established by the above test, the compounds of formula (I) according to the invention have an oral ED ₅₀ <100 mg / kg body weight and 3H spiperone.
IC ₅₀ <1000 nmol in dopamine receptor binding assay
And has promising psychoactive activity in that it is relatively potent in the CAR test. The activity in the CAR test and the spiperone assay is considered to be predictive of the psychoactive potential in the human body. With regard to selective psychoactive activity, the preferred compounds according to the invention have a pronounced dopamine receptor binding activity and inhibit rat CAR below the catalepsy dose.

A particularly preferred compound in this regard is 8-
[4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl] -8-azaspiro [4.5] decane-7,9-dione, which is about 8 Double CAR doses showed relatively weak cataleptic source activity in rats, suggesting a minimal potential for extrapyramidal side effects.

As mentioned above, the compounds obtained according to the invention have psychotropic properties which make them particularly suitable for use as potent tranquilizers. Therefore, another aspect according to the invention relates to a method of ameliorating a psychotic condition in a mammal when required for this treatment, which method comprises adding about 0% of the compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof. .01-4
Systemically administered to said mammal in an effective amount of 0 mg / kg body weight.

The term “systemic administration” as used herein refers to the oral, enteral and parenteral (ie, intramuscular, intravenous and subcutaneous) routes. Generally, when the compound of the present invention is administered orally, which is the preferred route, a larger amount of the active ingredient may be required to produce the same effect as when it is administered parenterally in a smaller amount. Be understood. According to true clinical practice, it is preferred to administer the compounds of the invention at a concentration level that produces an effective potent tranquilizing (psychotropic) effect without causing harmful or annoying side effects.

Therapeutically, the compounds according to the invention are generally in the form of a pharmaceutical composition comprising a psychotropically effective amount of the compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier. Is administered. About 1 to 5 active ingredients
Pharmaceutical compositions with 00 mg / unit dose are preferred, usually tablets, dragees, capsules, powders, water or oil suspensions,
It is prepared as a syrup, elixir and water solution.

Preferred oral compositions are in the form of tablets or capsules, with the usual excipients such as binders (eg syrup, acacia, gelatin, sorbit, tragacanth or polyvinylpyrrolidone), bulking agents (eg
Lactose, sugar, corn starch, calcium phosphate,
Sorbit or glycine), lubricants (eg magnesium stearate, talc, polyethylene glycol or silica), disintegrants (eg starch) and wetting agents (eg sodium lauryl sulphate). Solutions or suspensions of a compound of formula (I) with conventional pharmaceutical vehicles are used in parenteral compositions such as aqueous solutions for intravenous injection or oily suspensions for intramuscular injection. The composition having the transparency, stability and compatibility desired for parenteral use comprises 0.1 to 10% (by weight) of the active compound in water or a polyhydric aliphatic alcohol such as glycerin, propylene glycol, polyethylene glycol or Obtained by dissolving in these mixtures. Polyethylene glycol is soluble in both water and organic liquids,
And comprises a mixture of non-volatile, normally liquid polyethylene glycols having a molecular weight of about 200-1500.

[0056]

EXAMPLES The following examples are not intended to be limiting, but to illustrate the preparation of certain compounds of the present invention.

Example 1 3- (1-Piperazinyl) -1,2-benzisothiazole

[0058]

[Chemical 28]

3-Chloro-1,2-benzisothiazole (37.8 g, 0.235 mol) and piperazine (30
4.2 g, 3.53 mol) is heated in a closed reactor under argon atmosphere to 120 ° C. for 20 hours. The reaction mixture is dissolved in 2 l of water and the aqueous solution obtained is extracted repeatedly with methylene chloride. Combine the extracts,
Dry over magnesium sulfate and concentrate in vacuo. The residue is taken up in ether, filtered and concentrated in vacuo to give 3-
24.4 g (47%) of (1-piperazinyl) -1,2-benzisothiazole free base are obtained as a sticky oil.

A sample of the free base was converted to the hydrochloride salt with ethanolic hydrogen chloride in ether and crystallized from methanol-ethanol to give analytically pure 3- (1-piperazinyl) -1,2-benzisothiazole hydrochloride. was gotten. Melting point 280 [deg.] C. (decomposition).

[0061]

[Equation 1]

Example 2 3- (1-Piperazinyl) -1,2-benzisoxazole

[0063]

[Chemical 29]

3-Chloro-1,2-benzisoxazole (19.6 g, 0.128 mol) and piperazine (11
0 g, 1.28 mol) in a closed reactor at 120 ° C.
Heat for 20 hours. The reaction mixture is diluted with water and the aqueous mixture is extracted repeatedly with methylene chloride. The extracts are combined, dried over magnesium sulfate and concentrated in vacuo to give 21.2 g (yield 82%) of 3- (1-piperazinyl) -1,2-benzisoxazole free base.
A sample of the free base is converted to the hydrochloride salt and crystallized from methanol-ethanol to give analytically pure 3- (1-piperazinyl) -1,2-benzisoxazole hydrochloride. Melting point 326 [deg.] C (decomposition).

[0065]

[Equation 2]

Example 3 8- [4- [4- (1,2-benzisothiazole-3
-Yl) -1-piperazinyl] butyl] -8-azaspiro [4.5] decane-7,9-dione

[0067]

[Chemical 30]

Method A-Acetonitrile 3 in 1 liter
-(1-Piperazinyl) -1,2-benzisothiazole (24.3 g, 0.11 mol) and 8- (4-bromobutyl) -8-azaspiro [4.5] decane-7,9-dione (33 0.5 g, 0.11 mol), anhydrous potassium carbonate (32.4 g, 0.23 mol) and potassium iodide (3.9 g, 0.023 mol) are stirred for 20 hours and heated to reflux. The reaction mixture is filtered, concentrated in vacuo and the residue is taken up in 350 ml chloroform, filtered and concentrated in vacuo. The residue is triturated with ether, frozen and the solid obtained is collected. Crystallization of this material from acetonitrile using activated carbon gave a first yield of 25.1 g, melting point 120-124 ° C and a second yield of 6.0 g, melting point 123-126 ° C, total yield 3
1.1 g (64% yield) of the free form of the title compound are obtained. Analytical pure 8 when crystallized from acetonitrile
-[4- [4- (1,2-Benzisothiazole-3-
Yl) -1-Piperazinyl] butyl] -8-azaspiro [4.5] decane-7,9-dione is obtained. Melting point 1
24-126 ° C.

[0069]

[Equation 3]

Ethanol hydrogen chloride (12.3 ml, 5.
7N) is added to a suspension of the free base (31g) in hot isopropanol. The resulting solution is cooled and the formed precipitate is collected and dried under vacuum at 80 ° C. to give 8- [4- [4-
29.6 g of (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl] -8-azaspiro (4.5] decane-7,9-dione hydrochloride are obtained, melting point 219-220 ° C. .

[0071]

[Equation 4]

A sample of the free base product was crystallized from acetonitrile containing ethanolic hydrogen chloride to give 8- [4
-[4- (1,2-benzisothiazol-3-yl)
-1-Piperazinyl] butyl] -8-azaspiro [4.
5] Decane-7,9-dione dihydrochloride dihydrate is obtained. Melting point 118-120 [deg.] C.

[0073]

[Equation 5] Method B-3- (1-Piperazinyl) -1,2-benzisothiazole (5.0 g, 0.
0228 mol), 1,4-dibromobutane (9.8 g,
A mixture of 0.0456 mol) and finely ground anhydrous potassium carbonate (7.9 g, 0.057 mol) is stirred and refluxed for 16 hours. The cooled reaction mixture is filtered and the filtrate is concentrated in vacuo. The residual solid is heated to reflux with 70 ml of isopropanol and filtered. The filtrate was concentrated to about 1/2 volume and frozen to give 5.58 g of 8- (1,2-benzisothiazol-3-yl) -8-aza-5-azoniaspiro [4.5] decane bromide (yield 69 .1%) is obtained.
Melting point 246.5-253 [deg.] C.

[0074]

[Equation 6]

3,3-Tetramethyleneglutarimide (2.52 g, 0.0151 mol), 8- (1,2-benzisothiazol-3-yl) -8-aza-5-azoniaspiro in 125 ml of toluene. [4.5] A mixture of decane bromide (5.34 g, 0.0151 mol) and potassium carbonate powder (2.4 g, 0.0173 mol) is refluxed for 24 hours, stirred, filtered and evaporated to dryness. The residue is taken up in boiling toluene and diluted with hot heptane. The hot solution is treated with activated carbon, filtered and cooled to give 4.46 g (67.2% yield) solid. Melting point 1
09.5-120 ° C. 8- when crystallized from methanol
[4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] butyl] -8-azaspiro [4.5] decane-7,9-dione free base is obtained. Melting point 127.5-130 [deg.] C.

Example 4 8- [4- [4- (1,2-benzisoxazole-3
-Yl) -1-piperazinyl] butyl] -8-azaspiro [4.5] decane-7,9-dione

[0077]

[Chemical 31]

Following the procedure of Example 3, 8- (4-bromobutyl) -8-azaspiro [4.5] decane-7,9-
When dione is reacted with 3- (1-piperazinyl) -1,2-benzisoxazole and crystallized from the free ring radical isopropanol, 8- [4- [4- (1,2-benzoxazol-3-yl ) -1-Piperazinyl] butyl] -8-azaspiro [4.5] decane-7,9-dione hemihydrate is obtained. Melting point 96-98 [deg.] C.

[0079]

[Equation 7]

Example 5 3- [4- [4- (1,2-benzisothiazole-3
-Yl) -1-piperazinyl] butyl] -2,4-thiazolidinedione

[0081]

[Chemical 32]

(A) 2,4-thiazolidinedione sodium salt-2,4-thiazolidinedione (11.7 g,
0.1 mol) and 0.1N sodium hydroxide 100 ml
(0.1 mol) are mixed and, if necessary, heated to obtain a solution. Concentration of the basic solution under reduced pressure gives a semi-solid, repeated trituration with acetone and removal of the solvent in vacuo gives a crystalline solid. This material was collected, washed with acetone, and dried in vacuum at 66 ° C. to give 15.1 g of sodium salt of 2,4-thiazolidinedione (yield 95%).
Is obtained. Melting point 225 [deg.] C (decomposition).

(B) 3- (4-bromobutyl) -2,4
-Thiazolidinedione-2,4-thiazolidinedione sodium salt (13.91 g, 0.1 mol) is added to a solution of 1,4-dibromobutane (64.77 g, 0.3 mol) in 500 ml dry dimethylformamide. After stirring the mixture at room temperature for 16 hours, the resulting clear solution was concentrated in vacuo, the residue was dissolved in chloroform, filtered and concentrated in vacuo to give an amber oil. Distillation of this oil gives 20.62 g (81% yield) of 3- (4-bromobutyl) -2,4-thiazolidinedione. Boiling point 105-115 ° C (0.02 mmHg).

(C) 3- [4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl] -2,4-thiazolidinedione dihydrochloride-Example 3
3- (4-bromobutyl) -2,4-
Thiazolidinedione was converted to 3- (1-piperazinyl) -1,
Reaction with 2-benzisothiazole and conversion of the free base to the hydrochloride salt in acetonitrile yielded 3- [4- [4- (1,2benzisothiazol-3-yl) -1-piperazinyl] butyl from acetonitrile. ] -2,4
-Thiazolidinedione dihydrochloride is obtained in 43% yield. Melting point 200-202 [deg.] C.

[0085]

[Equation 8]

Example 6 3- [4- [4- (1,2-benzisoxazole-3
-Yl) -1-piperazinyl] butyl] -2,4-thiazolidinedione

[0087]

[Chemical 33]

Reaction of 3- (4-bromobutyl) -2,4-thiazolidinedione with 3- (1-piperazinyl) -1,2-benzisoxazole according to the procedure of Example 3 from methanol gave 3- [4 -[4- (1,2-Benzisoxazol-3-yl) -1-piperazinyl] butyl] -2,4-thiazolidinedione is obtained with a yield of 44%. Melting point 104.5-106.6 [deg.] C.

[0089]

[Equation 9]

Example 7 8- [4- [4- (1,2-benzisothiazole-3
-Yl) -1-piperazinyl] butyl] -6-thia-8
-Azaspiro [4.4] nonane-7,9-dione

[0091]

[Chemical 34]

(A) 5-spirocyclopentyl-2,4
-Thiazolidinedione sodium salt 5-obtained according to Jones et al.
Spirocyclopentyl-2,4-thiazolidinedione (1.71 g, 0.01 mol) and 10 ml (0.01 mol) of 1.0N sodium hydroxide are mixed and heated as necessary to give a solution. Repeated acetone trituration to concentrate the basic solution and removal of the solvent in vacuo gives 1.66 g (86% yield) of the sodium salt of 5-spirocyclopentyl-2,4-thiazolidinedione. Melting point 243-245 [deg.] C.

(B) 3- (4-Bromobutyl) -5-spirocyclopentyl-2,4-thiazolidinedione dimethylformamide 5-spirocyclopentyl-2,4-thiazolidinedione sodium salt (3.83 g, 0. 019 mol) was slowly added to 1,4-dibromobutane (1
2.84 g, 0.059 mol). The mixture is stirred at room temperature for 16 hours and then concentrated under reduced pressure. Dissolve the residue in chloroform, filter and concentrate the filtrate,
When distilled, 4.96 g of 3- (4-bromobutyl) -5-spirocyclopentyl-2,4-thiazolidinedione was obtained.
(Yield 85%) is obtained. Boiling point 122-126 ° C (0.
04mmHg).

(C) Reaction of the title product hydrochloride hydrate 3- (4-bromobutyl) -5-spirocyclopentyl-2,4-thiazolidinedione with 3- (1-piperazinyl) -1,2-benzisothiazole. And conversion of the free base to the hydrochloride salt according to the procedure of Example 3 from methanol to 8- [4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl] -6.
-Thia-8-azaspiro [4.4] nonane-7,9-dione hydrochloride hydrate is obtained with a yield of 84%. Melting point 214
° C.

[0095]

[Equation 10]

Example 8 8- [4- [4- (1,2-benzisoxazole-3
-Yl) -1-piperazinyl] butyl] -6-thia-8
-Azaspiro [4.4] nonane-7,9-dione

[0097]

[Chemical 35]

3- (4-bromobutyl) -5-spirocyclopentyl-2,4-thiazolidinedione was converted into 3- (1
Reaction with -piperazinyl-1,2-benzisoxazole and conversion of the free base to the hydrochloride salt according to the procedure of Example 3 from isopropanol to 8- [4- [4-
(1,2-Benzisoxazol-3-yl) -piperazinyl] butyl] -6-thia-8-azaspiro [4.
4] 88% yield of nonane-7,9-dione hydrochloride hydrate
Can be obtained at. Melting point 212-214 [deg.] C.

[0099]

[Equation 11]

Example 9 1- [4- [4- (1,2-benzisothiazole-3
-Yl) -1-piperazinyl] butyl] -4-methyl-
4-propyl-2,6-piperidinedione

[0101]

[Chemical 36] (A) N- (4-bromobutyl) -3-methyl-3-n
-Propylglutarimide N above. S. 3-Methyl-3-n-propylglutarimide (25 obtained according to Benica et al.
g, 0.15 mol), 1,4-dibromobutane (33.
5 g, 0.15 mol) and potassium carbonate (4.6 g,
A mixture of 0.29 mol) is stirred and refluxed in 250 ml of acetonitrile for 16 hours. Insoluble material is filtered off and the filtrate is concentrated in vacuo to an oil. The residual oil was distilled to give N- (4-bromobutyl) -3-methyl-3-n as a pale yellow oil.
42.5 g (95%) of propylglutarimide are obtained. Boiling point 165 to 190 ° C (0.09 mm).

(B) The title product hydrochloride N- (4-bromobutyl) -3-methyl-3-n-propylglutarimide was converted to 3- (1-piperidinyl) -1,
Reaction with 2-benzisothiazole and conversion of the free base to the hydrochloride salt according to the procedure of Example 3 to give 1- [4- [4-
(1,2-Benzisothiazol-3-yl) -1-piperazinyl] butyl] -4-methyl-4-propyl-
2,6-piperidinedione hydrochloride is obtained. Melting point 16
3 to 165 ° C.

[0103]

[Equation 12]

Example 10 1- [4- [4- (1,2-benzisothiazole-3
-Yl) -1-piperazinyl] butyl] -4,4-dimethyl-2,6-piperidinedione

[0105]

[Chemical 37]

N- (4 obtained according to the procedure of Example 9
-Bromobutyl) -3,3-dimethylglutarimide (4 g, 0.0145 mol), 3- (1-piperazinyl) -1,2-benzisothiazole (3.18 g,
0.0145 mol), anhydrous potassium carbonate (20.04
g, 0.145 mol) and potassium iodide (0.25
g, 0.0015 mol) in 150 ml of acetonitrile are stirred and refluxed for 12 hours. The reaction mixture is filtered, concentrated in vacuo and the residue triturated with ether. The solid thus obtained was crystallized from ether to give analytically pure 1- [4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] butyl] -4, 4-Dimethyl-2,6-piperidinedione is obtained with a yield of 64%. Melting point 146-147 ° C

[0107]

[Equation 13]

Example 11 1- [4- [4- (1,2-benzisothiazole-3
-Yl) -1-piperazinyl] butyl] -4,4-diethyl-2,6-piperidinedione

[0109]

[Chemical 38]

(A) N- (4-bromobutyl) -3,3
-Diethylglutarimide 3,3-diethylglutarimide (7.0 g, 0.041 mol) in 100 ml of 70% ethanol (NS.
20) and a mixture of sodium hydroxide (1.64 g, 0.041 mol).
Warm for minutes and stir. The mixture is concentrated in vacuo to give the solid sodium salt of 3,3-diethylglutarimide, which is suspended in 150 ml of dimethylformamide and 1,4-dibromobutane (17.7 g,
0.082 mol). The resulting mixture is stirred at room temperature for 48 hours then concentrated in vacuo. The residue was dissolved in chloroform, filtered, and the filtrate was concentrated and distilled to give 11.4 g (93% yield) of N- (4-bromobutyl) -3,3-diethylglutarimide.

(B) The title product hydrochloride hydrate N- (4-bromobutyl) -3,3-diethylglutarimide was reacted with 3- (1-piperazinyl) -1,2-benzisothiazole to give the Example. Conversion of the free base to the hydrochloride salt in isopropanol according to the procedure of 3
[4- [4- (1,2-Benzisothiazol-3-yl) -1-piperazinyl] butyl] -4,4-diethyl-2,6-piperidinedione hydrochloride hydrate is obtained.
Melting point from acetonitrile 179-183 [deg.] C.

[0112]

[Equation 14]

Example 12 4- [4- (1,2-benzisothiazol-3-yl) -1-piperazinyl] -1- (4-fluorophenyl) -1-butane

[0114]

[Chemical Formula 39]

(A) 2- (3-chloropropyl) -2-
4-Chloro-4'-fluorobutyrophenone (50 ml of benzene as described in (4-Fluorophenyl) -1,3-dioxane Chemical Abstracts (Chem. Abs.), Vol. 63, 9959b (1965). A mixture of 20 g), ethylene glycol (6.9 g) and p-toluene sulfonic acid (0.05 g) is refluxed for 30 hours while collecting the water formed. The reaction mixture was concentrated in vacuo to give 2- (3-chloropropyl)-
2- (4-Fluorophenyl) -1,3-dioxane is obtained.

(B) Title product hydrochloride 2- (3-chloropropyl) -2- (4-fluorophenyl) -1,3-dioxane (4.31 g, 0.0176 mol) in 180 ml dry acetonitrile. 3- (1-
Piperazinyl) -1,2-benzisothiazole (3.
86 g, 0.0176 mol), powdered potassium carbonate (2.
A mixture of 43 g, 0.0176 mol) and potassium iodide (0.88 g, 0.0053 mol) is refluxed for 20 hours. The reaction mixture is filtered, concentrated in vacuo and the residual oil is dissolved in chloroform and filtered. The filtrate is concentrated to give an oily residue, which is taken up in 100 ml of ethanol containing 10 ml of 3N hydrochloric acid and refluxed for 15 minutes. Acetonitrile is added to the cooled mixture and the resulting solid is collected. 3.3 g, melting point 248-250 ° C. This was crystallized from ethanol to give analytically pure 4-
[4- (1,2-benzisothiazol-3-yl)-
1-piperazinyl] -1- (4-fluorophenyl)-
1-butanone hydrochloride is obtained. Melting point 251-254
° C.

[0117]

[Equation 15] Example 13 α- [3- [4- (1,2-benzisothiazole-3
-Yl) -1-piperazinyl] propyl] -4-fluorobenzenemethanol

[0118]

[Chemical 40]

Sodium borohydride (1.0 g, 0.0
26 mol) in 4- [4- (4-
(1,2-Benzisothiazol-3-yl) -1-piperazinyl] -1- (4-fluorophenyl) -1-butanone hydrochloride (3.34 g, 0.008 mol) added dropwise to a stirred suspension. Add The mixture is stirred for 20 hours, acidified with ethanolic hydrogen chloride, stirred for a further 2 hours and concentrated in vacuo. Chloroform and 1N
Fractionation with aqueous sodium hydroxide solution and drying of the chloroform phase over magnesium sulphate and concentration in vacuo gave 2.31 g of the title compound as free base (yield 69
%)was gotten. Conversion of the free base to the hydrochloride with ethanolic hydrogen chloride in ethanol yields α- [3- [4- (1,
2-Benzisothiazol-3-yl) -1-piperazinyl] propyl] -4-fluorobenzenemethanol hydrochloride is obtained. Melting point 200-202 [deg.] C.

[0120]

[Equation 16]

Example 14 4- [4- (1,2-Benzisoxazol-3-yl) -1-piperazinyl] -1- (4-fluorophenyl) -1-butanone

[0122]

[Chemical 41]

Following the procedure of Example 12, 2- (3-chloropropyl) -2- (4-fluorophenyl) -1,
3-dioxane was added to 3- (1-piperazinyl) -1,2-
Reaction with benzisoxazole and conversion of the free base to the hydrochloride salt from methanol to 4- [4- (1,2-
Benzisoxazol-3-yl) -1-piperazinyl] -1- (4-fluorophenyl) -1-butanone hydrochloride is obtained in 25% yield. Melting point 260-262 [deg.] C.

[0124]

[Equation 17]

Example 15 α- [3- [4- (1,2-benzisoxazole-3
-Yl) -1-piperazinyl] propyl] -4-fluorobenzenemethanol

[0126]

[Chemical 42]

4- [4-
(1,2-Benzisoxazol-3-yl) -1-piperazinyl] -1- (4-fluorophenyl) -1-butanone hydrochloride (2.0 g, 0.005 mol) was added to sodium borohydride ( 0.57 g, 0.015 mol) is reduced according to the procedure of Example 13. The residue remaining after concentrating the acidic mixture is basified with sodium hydroxide and extracted with chloroform. The combined extracts are dried over sodium sulfate, concentrated in vacuo, and triturated with ether to give 1.2 g of free base product. Crystallization of this from ethanol gave analytically pure α- [3- [4-
(1,2-Benzisoxazol-3-yl) -1-piperazinyl] propyl] -4-fluorobenzenemethanol is obtained. Melting point 142.5-143.5 [deg.] C.

[0128]

[Equation 18]

Example 16 8- [4- [4- (2,1-benzisothiazole-3
-Yl) -1-piperazinyl] butyl] -8-azaspiro [4.5] decane-7,9-dione

[0130]

[Chemical 43]

(A) 3- (1-piperazinyl) -2,1
-Benzisothiazole 3-chloro-2,1-benzisothiazole (4.79)
g, 0.028 mol, J. Het Hem (J. Het. C
hem. ), Vol. 15, p. 529, 1978, obtained according to Albert et al.) And piperazine (36.2 g, 0.42 mol) are heated to 120 ° C. for 18 hours in a closed reactor. The cooled reaction mixture is dissolved in 400 ml of water and the aqueous solution is extracted with ether then methylene chloride. The combined extracts were dried over magnesium sulfate and concentrated in vacuo to give 3- (1-piperazinyl) -2,1-benzisothiazole free base.
67 g (90% yield) are obtained. A sample of the free base is converted to the hydrochloride salt with ethanolic hydrogen chloride in ethanol to give analytically pure 3- (1-piperazinyl) -2,1-benzisothiazole dihydrochloride. Melting point 274-2
76 ° C (decomposition).

(B) The title product dihydrochloride dihydrate 3- (1-piperazinyl) in 100 ml acetonitrile.
-2,1-benzisothiazole (4.0 g, 0.01
8 mol), 8- (4-bromobutyl) -8-azaspiro [4.5] decane-7,9-dione (5.5 g, 0.0
18 mol), anhydrous potassium carbonate (4.98 g, 0.03)
6 mol) and potassium iodide (0.83 g, 0.00
The mixture (5 mol) is stirred at reflux temperature for 20 hours.
The reaction mixture is filtered, concentrated in vacuo and the residue triturated with ether to give 7.38 g (93% yield) of the title compound free base. The free base was converted to the hydrochloride with ethanolic hydrogen chloride in ethanol and crystallized from ethanol to give analytically pure 8- [4- [4- (2,1-benzisothiazol-3-yl) -1-piperazinyl. ] Butyl] -8-azaspiro [4.5] decane-7,9-dione dihydrochloride hemihydrate (5.34 g, yield 57%) is obtained. Melting point 225-227 [deg.] C (decomposition).

[0133]

[Formula 19]

Example 17 8- [4- [4- (6-chloro-1,2-benzisoxazol-3-yl) -1-piperazinyl] butyl]-
8-azaspiro [4.5] decane-7,9-dione

[0135]

[Chemical 44]

(A) 3- (1-Piperazinyl) -6-chloro-1,2-benzisoxazole 3,6-dichloro-1,2-benzisoxazole and piperazine according to the procedure of Example 2. The mixture is allowed to react. 3- (1-piperazinyl) -6-chloro-1,2-
The benzisoxazole intermediate is isolated with a yield of 79% and is used without further purification.

(B) Title product 8- (4-Bromobutyl) -8 according to the procedure of Example 3.
-Azaspiro [4.5] decane-7,9-dione (2.
03 g, 0.067 mol) was added to -3- (1-piperazinyl) -6-1,2-benzisothiazole (1.6 g,
0.067 mol) gives a crude base which is converted to the hydrochloride salt and crystallized from ethanol. The salt is taken up in water and made basic with ammonium hydroxide to give the free base, which is crystallized from isopropanol to give analytically pure 8- [4- (6-chloro-
0.3 g of 1,2-benzisoxazol-3-yl) -1-piperazinyl] butyl] -8-azaspiro [4.5] decane-7,9-dione (yield 10%) is obtained.
Melting point 127.5-128.5 [deg.] C.

[0138]

[Equation 20]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI technical display location A61K 31/44 AAC 31/495 7252-4C 31/505 7252-4C 31/53 7252-4C C07D 413 / 12 8829-4C 417/12 9051-4C (72) Inventor J. Joseph P. Yebitz, Newburgh, IN, USA 8366

Claims (3)

[Claims] 1. Formula (III): A piperazine heterocyclic compound having the formula: Y is oxygen or sulfur, and Z is hydrogen or halogen. 2. The compound according to claim 1, which is 3- (1-piperazinyl) -1,2-benzisothiazole. 3. The compound according to claim 1, which is 3- (1-piperazinyl) -1,2-benzisoxazole.